Study of deadly flu sparks debate amidst fears of new pandemic

Last night, the New York Academy of Sciences hosted a discussion on the …

The 2009 flu pandemic, although not especially deadly, revealed just how quickly a new influenza virus could elude surveillance and spread internationally. It also left health experts eying the disease that many fear could cause the next pandemic: H5N1, the avian flu. According to World Health Organization standards, that virus is phenomenally deadly, killing about half the people that contract it. So far, however, almost all the known cases came from people who were in direct contact with poultry; the flu doesn't seem to spread among mammals.

The great unanswered question was whether we could continue to rely on H5N1's limited transmission. Recently, some researchers set out to answer that question, and came up with a disturbing answer: it was relatively easy to evolve a form of H5N1 that spread in ferrets, another mammalian species, without it losing any of its virulence. Two labs identified the exact mutations that enabled this new host range, and were preparing to publish their results in Science and/or Nature. At that point, the US government's National Science Advisory Board for Biosecurity (NSABB) responded by requesting that the journals delay publication and limit the content released. That, in turn, prompted the viral research community to put a two-month hold on further research.

That's where things stood on February 2, when the New York Academy of Sciences hosted a panel discussion on H5N1 and other dual-use research (research that has both public benefit and weapons applications). The panel included two members of the NSABB, representatives from both Science and Nature, a number of virus researchers, a public health expert, and a member of the Defense Department, and they spent two hours in a lively and sometimes contentious discussion of how to handle our current situation.

What's the consensus on the threat?

Most scientists disagree with you—we have no choice but to act as if you are wrong

We now clearly know that H5N1 can spread among mammals. What does that tell us about the human risk? That obvious question triggered the most contentious arguments of the evening. One of the panelists, Mount Sinai's Peter Palese, has recently published a paper in which he argued that fears of H5N1 are overblown. In both the paper and at the discussion, he argued that the WHO only counted cases that resulted in hospitalization, and some studies had found a low but significant level of people who carried H5N1 but remained asymptomatic. And, while he was at it, he questioned whether ferrets were a valuable model for the human response. Overall, it was clear that he didn't think the research should be causing much fuss at all.

But, in stating that, he managed to create quite a bit of fuss. The two members of the NSABB on the panel, Einstein's Arturo Casadevall and Minnesota's Michael Osterholm, noted that their group's responsibility in evaluating the H5N1 research was to identify the best opinion of the experts in the field. And, as far as they could tell, Palese's opinion was way outside of the expert consensus—most experts found the work a cause for great concern. Osterholm had actually prepared a point-by-point rebuttal of Palese's publication, focusing on the technical weaknesses of the various studies he used to support his argument.

Both Osterholm and Casadevall pointed out that, even if the WHO's estimates of the virus' lethality were high by a factor of 10, it would still be far more deadly than the 1918 flu. If it were off by 100, it could still cause 200 million deaths. At one point, turning to Palese, Osterholm said, bluntly, "most scientists disagree with you—we have no choice but to act as if you are wrong."

But Casadevall had what might have been the most compelling take on matters. When the NSABB was called on to look into the H5N1 work, he said, he went into it with the feeling that it was important scientific research and needed to be shared widely with the community. After talking with enough influenza experts, though, "I changed my mind." By the end of his work on the matter, he agreed with the panel's recommendation that access to the results should be limited. The strength of the consensus among the experts had been enough to get him to rethink his initial reaction.

What to do when research makes the experts nervous

So, if the H5N1 research was enough to make flu experts nervous, what should a journal do with a paper that describes the research in detail? Both Nature and Science (represented by Véronique Kiermer and Barbara Jasny, respectively) are currently struggling with just that. Although the journals haven't officially announced how they'd handle things, they and others have mooted running a redacted form of the papers, with key experimental details and data removed from the text, and the entire panel seemed to be treating that option as if it was how the journals would proceed.

The panel was asked to estimate how many people had seen all the sensitive data, and estimates ranged from a few hundred to about 1,000. To some extent, the whole debate about this research is taking place after the fact.

That's a pretty radical decision. Science, in part, is based on the free exchange of information. What good is a publication with key pieces of information cut out?

Kiermer said that the paper will serve three functions, even in its limited form. The first is that the message of the paper is important. It's no longer safe to assume that, since the avian flu hasn't spread among humans to this point, that it never will. And that has some major implications for global public health; at various points members of the panel described our international monitoring systems as limited and poorly organized.

Practically, even a redacted publication in a major journal would allow the researchers to gain credit for their work, which can be valuable in terms of securing funding or promotion within their institutions. Finally, Kiermer said that the publications will alert those who have a need for the details and will treat them responsibly, allowing them to request an unredacted version of the paper. Both Science and Nature are currently exploring ways to identify those people that deserve access to the full paper.

But both Kiermer and Jasny were clearly unhappy with being thrust into the role of gatekeepers; Jasny referred to it as being told to "find a solution to a mess that is not of our making," and stated "I hope that it's a one-time event."

Even with the paper being held up, however, lots of people know key details. Both journals sent versions out to reviewers and distributed copies among their editorial staff; the entire NSABB got copies, and distributed some to experts they consulted with; the results came to public attention because they were presented at a meeting. The panel was asked to estimate how many people had seen all the sensitive data, and estimates ranged from a few hundred to about 1,000.

To some extent, the whole debate about this research is taking place after the fact.

"We don't want to be surprised again"

How do we get to the point where we no longer hold up papers after they're written and put research on hiatus only after the most significant work has been done? The panel appeared unanimous in hoping that some general lessons could be drawn from this mess, but were a bit less unanimous in deciding what those lessons were.

Poor people all over the world are killing their chickens for you to contain the avian flu. They are going bankrupt for you.

The H5N1 work is a clear example of what's called dual-use research, since it's not difficult to imagine the threat potential of a lethal flu virus. But the panel generally agreed that all research is dual-use. Very basic biology and chemistry research, done decades earlier, was essential to giving us the ability to synthesize arbitrary DNA sequences and link them together; that ability now makes the publication of the DNA sequence that encodes newly evolved H5N1 virus a threat, since anyone can order up the requisite DNA to make a copy.

That fact also makes Osterholm's preferred form of evaluation, a risk-benefit analysis, rather tricky. How can we possibly identify benefits of research that will completely revolutionize their field, especially when those benefits only arise decades later? (As virologist Vincent Racinoello pointed out, work on restriction enzymes was considered a backwater in the 1970s; now, the entire biotech industry relies on them.)

The key, according to Casadevall, is identifying what's been called dual-use research of concern, or DURC. The panel generally agreed that most people could see the difference between enabling research, like the development of DNA synthesis techniques, and research that creates an actual risk, like the resurrection of the 1918 flu virus (which was the first time the NSABB was called into action).

That seems like a good idea, but doesn't solve the basic problem: who identifies this research, and how do they respond to it? Even within the US, which has a highly developed biomedical research system, there's no formal body that handles issues like this, and it's not clear if anybody has the appetite to create one. Researchers will be leery of any additional oversight—Casadevall quipped that he already has to write 100 page descriptions justifying his use of lab mice at the same time he could walk to a hardware store and buy a 100 different products meant to brutally kill them. And the US public has little appetite for additional regulatory schemes, or the costs and bureaucracy needed to ensure they're effective.

And that's just within the US. Any work of this sort has clear international implications, which play out on multiple levels. Many other nations support labs that operate at biosafety levels 3 and 4, which are meant to handle DURC, but the training, inspection, and maintenance of these facilities varies widely.

Many other nations that don't support a biomedical research community are on the front lines of the efforts to contain avian flu. As Laurie Garrett from the Council on Foreign Relations put it, we need them to buy in to whatever we do. "Poor people all over the world are killing their chickens for you" to contain the avian flu, Garrett said. "They are going bankrupt for you." One consequence of that is that nations like Indonesia have been calling for full and unfettered access to the H5N1 work, since it will allow them to improve their surveillance system.

So, if there was general agreement that we need to do better at handling dual-use research, there was quite a bit less consensus on how to go about that.

34 Reader Comments

I've seen a lot of people glibly say "Oh it's no big deal, nuclear physicists have done it for decades!" usually without much further explanation of who and how. I'd think that if it was really working so great, there would have been a few veteran physicists at the panel ready to make suggestions, no?

i think a simple requirement of hanging a poster of Ian Malcom saying "Yeah, but your scientists were so preoccupied with whether or not they could, they didn't stop to think if they should" should do it.

it is a super interesting issue. when i think about what the problem REALLY is, I think it is a function of how dangerous the work is vs how hard it would be to implement... scales need to be made.

so a scale of how dangerous something is should go from "destruction of spacetime" to "no conceivable danger", implementation should be from "impossible to obtain needed materials in our solar system," to "every person is born with this."

in this case we have "killing half the people on earth" with "something that would take $10,000 to obtain."

"One of the panelists, Mount Sinai's Peter Palese, has recently published a paper in which he argued that fears of H5N1 are overblown. In both the paper and at the discussion, he argued that the WHO only counted cases that resulted in hospitalization, and some studies had found a low but significant level of people who carried H5N1 but remained asymptomatic."

"But, in stating that, he managed to create quite a bit of fuss. The two members of the NSABB on the panel, Einstein's Arturo Casadevall and Minnesota's Michael Osterholm, noted that their group's responsibility in evaluating the H5N1 research was to identify the best opinion of the experts in the field. And, as far as they could tell, Palese's opinion was way outside of the expert consensus"

That sounds familar. I wonder if the scientific community threatened the journal in which this paper was published and got it to retract the paper in question. Ive been told by people who claim to know that publication of this sort of 'junk' science is exceedingly caustic to science itself, and, if that is so, how can the science community rely on a mere 'point-by-point rebuttal'? Shouldnt they be actively suppressing the publication of this paper to prevent people from thinking that its somehow legit?

This has always been an issue, and I've loved science fiction stories based on this idea. What if an ideal large power source was found? What if all the energy you could possibly want was freely available? But what if that same energy was easy to be released all at once, in a weaponized form? Pretty similar to the nuclear bomb, but at a greater scale in both its positive and negative aspects? If it would be able to provide infinite, free, safe energy for everyone forever, but with deliberate changes could also easily destroy the world?

Pop quiz, hotshot, what do you do? What do you do?

On one hand you could alleviate a great deal of suffering and hardship, save millions of lives. On the other hand, you've made it easy to destroy large parts of the world and destroy many lives. How long before manic depressives start holding population centers hostage? Before one of them blows up New York just to show he isn't bluffing about blowing up Washington DC?

Would you publish the data? It's science! Science is neither good nor evil, it just IS.

But it doesn't seem to be too different from this situation, except to say that there is virtually NO upside to publishing it. The conclusions they have reached have been distributed. We know it can mutate to be spread among mammals. Do we NEED to publish hints on how to weaponize it? Heaven forbid that we need to publish directions. How about rather then studying how to make the virus worse so as to better understand it, study how to make it less deadly. Study how to make it harmless, or to cure it. I know these things are difficult, and perhaps they need to make it worse in order to make it better. But I have trouble swallowing any explanation that has been used as a Mission Impossible plot.

I think a point a number of people miss in this situation is that this approach of adapting a virus to another species is a bedrock experimental approach in influenza research field. If you are involved in the field or take a few moments read up on a bit, you'll know exactly how they went about to make these strains ferret adapted. This wasn't a secret before, it's not a secret now. While somebody may raise the point that the actual mutation locations,etc. may not have disseminated to the general public, I would argue that that's irrelevant. If somebody was determined to "humanize" these viruses, they certainly did not need any of the information these research groups have put forth to do so.

I agree there are some concerns over whether the research is worth the risk (plenty in the field are discussing it as you can see from the panel), but the idea that we will keep the approach under wraps by redacting portions of the publications just comes off as a silly PR stunt to calm people down.

Grumble, it appears Ars spawned two different discussion threads for this topic, first the one two of us reached and then the main one. Mirroring from the other thread then:---Thank you for this follow up review article, it's an interesting and tricky topic, and I'm glad it's getting serious debate amongst experts. While I personally strongly leaned towards not preventing the research itself, and minimal censorship of the publication, if the experts in the field believe otherwise then they'd obviously be the ones in the best position to decide that. I share the concerns raised towards the end though: that not only could this happen naturally, but that there's no way to ensure uniform rules worldwide, which immensely reduces the value of restrictions. The issue of "buy-in" definitely is important as well: we can't just be lords issuing dictates from on-high, all participants need to be onboard at least for major decisions.

The best way forward still seems to be aiming not so much at information prevention but rather at extracting the maximum positive value. A tremendously enhanced early detection network would seem like an excellent place to start. Being able to identify any outbreaks rapidly and with high granularity would be valuable for many different aspects, including spread prevention, treatment development, and even helping to determine whether it was a natural event or not. Research on how to up infrastructure (and funding for it) for rapid mass vaccine production might be worth international cooperation too. Then outbreaks themselves, regardless of source, would be significantly less scary.

Umm... the statement: "If it were 100 times less lethal, it could kill 200 million people" implies that H5N1 is currently believed to be able to kill 20 billion people.

Lethality will be in terms of probabilities. The language could be clearer (preferably expressed in terms of explicit probabilities, for the benefit of those of us who are not virologists and who may not understand the technical nuances of "lethality" in this context); but I'm fairly certain the maths is not quite this simple.

i think a simple requirement of hanging a poster of Ian Malcom saying "Yeah, but your scientists were so preoccupied with whether or not they could, they didn't stop to think if they should" should do it.

it is a super interesting issue. when i think about what the problem REALLY is, I think it is a function of how dangerous the work is vs how hard it would be to implement... scales need to be made.

so a scale of how dangerous something is should go from "destruction of spacetime" to "no conceivable danger", implementation should be from "impossible to obtain needed materials in our solar system," to "every person is born with this."

in this case we have "killing half the people on earth" with "something that would take $10,000 to obtain."

it should be noted, since this is about publishing the results and not doing the work, we should leave out the idea of "benefits." there are no benefits in just publishing the paper. It only brings up an "ends justify the means" fallacy... like the person said about unlimited energy, if you simply look at how dangerous it is and how easy it is to implement, you get your answer pretty quick on publishing the paper.

say unlimited energy could be attained from dripping orange juice on a CPU slowly, but put a couple CPUs in a gallon of juice and you blow up a city. Easy, don't publish the results.

A lot of the usual dramatization so that medical scientists can get highly paid jobs.I remember France had millions of extra vaccine doses that went to waste, because very few people got vaccinated and nobody contracted H5N1. They tried to sell some of them to Arabic countries at discount price...

I wonder how contagious H5N1 really is. In 2 different books, I read that the progression of the avian flu did not follow any standard bird migration patterns. Indeed, that wild birds were not an agent of propagation. All the cases so far seem to be related to CAFO chicken farms, not flying birds, with one case being apparently clearly linked to a specific CAFO, with H5N1 cases spreading from the CAFO production center to the final distribution center.

Not sure how much truth to put into such reports, as I haven't seen the evidence myself, and I would welcome more studies on this, but given the poor sanitary conditions in CAFO, I mean, given the extremely unhealthy conditions, I wouldn't be surprised if some CAFOs turned out to be the cause of H5N1. And of course, it's not something that the global agrobusiness would easily let us investigate.

Not being a medical researcher, it took me less than a second to find the gaping hole in Peter Palese's statement. "Act as if" Peter Palese is wrong? He IS wrong. In fact a retard could be made to understand that if the avian flu is 10x less dangerous than anticipated, you have a 5% mortality rate, which is astronomical. The man is possibly insane or at best grossly irresponsible. From this alone I think his license should be revoked and his opinion ignored going forward. I'm hoping that Ars is reporting this incorrectly.

On the other hand I can see how a scientist could argue that publishing the paper would lead to greater responsiveness and reduced risk. I would disagree with it but at least that is a respectable argument.

The math for the upper limit on the number of people a virus strain (or anything for that matter) could kill is simple. The tougher problem here for a biological cause is considering population movement, contagion, incubation, probability of having symptoms if you have exposure, method of exposure, etc and deriving a likely outcome.

But for the maximum upper limit, that is straight forward given a population and a simple probability.

Based on the article, WHO stated that the lethality of the H5N1 was about one-half. So starting with that (just assume this is accurate), we can state:

Assuming the absolute worst case scenario of every one of the 7 Billion people are exposed and contract the virus.

Then:Pop x pL = 7E9 x 0.5 = 3.5E9 or 3.5 billion people.

If the pL is over estimated by a factor of 10 (pL=0.05, or 5%) then:Pop x pL = 7E9 x 0.05 = 3.5E8 or 0.35 billion people or 350 million people. Maybe almost twice the toll of the 1918 flu, given today’s population.

If the pL is over estimated by a factor of 100 (pL=0.005 or 0.5%) then:Pop x pL = 7E9 x 0.005 = 3.5E7 or 0.035 billion people or 35 million people. Maybe 70 times worst than a typical flu season.

These numbers represent absolute upper limit given only the lethality. Other factors would reduce the number of people killed, for example they are not exposed at all.

If fact a very high pL and a short incubation period (after the disease is infectious) could reduce the real threat. Example ebola.___The principle reason for the research was to determine is there was the potential for a real threat from nature. One idea had been if the threat from nature was potentially valid, then developing a vaccine now could have a significant benefit. Otherwise you wait for months before the first vaccines can appear. I seem to recall reading the many times when influenza jump species, it can be come less virulent (but not necessarily). However, over time after jumping species that virulence may increase. ___

Now if the number was 200 million deaths and the WHO numbers were off by a factor of 100, then the world population would have to be:

2e8 / (0.5 / 100) = 4e10 Now that is a whole bunch of people, 400 Billion That would be big news. Just where are the other 393 Billion people hiding?

The thing is flu doesn't make a very good biological weapon. Pretty much every country with a winter would get the full treatment once it is released, regardless where you release it.

So the only people who would use it as a weapon are insane and luckily insane people normally don't make good biologists. Lets be honest here Al Qaida hasn't been a hotbed of innovative and intelligent terrorist attempts since 2001. A single insane norwegian guy has done more damage to the western world in a day than all of Al Qaida has managed for a decade.

I can already kill the world population with a virus. Its called "ebola". It has been sequenced and you can make viruses from scratch now.

I think you can all do the math on that one.

Avian flu is completely irrelevant as a bioweapon, and anyone who is trying to suppress scientific research in the name of national security is a horrible human being.

This needs to be published. It can't hurt anything and will certainly help advance research.

I don't buy the ebola argument in that it takes far too little time for the particularly virulent strains to kill a person, and the rest don't have that high (okay so quite high, but not 'better than an engineered flu' high) mortality rate. I'm going to wager a guess and say the most successful virus would be one that takes a year to kill a person, is easily communicable, has a very long dormant phase, and has no known or cheaply and easily administered cure. Something like HIV/AIDS.

A PHD doesn't make one smart, and scientists, of all people, should always know that what they don't know is always greater than what they know. I recall a story from a few years ago about a Scientist in the US studying bubonic plague. He genetically modified it to be be harmless in humans, and proceeded to experiment with no bio-hazard controls in place at a public university. Of course, what he did not know was that the modification he made actually optimized the plague for the very genetic traits shown by descendents of plague survivors. Of course he got the plague and died. Luckily, it did not go farther than that.

The logic of creating a deadly flu virus optimized for human transmission - to study it. Is beyond me. Logically they should be charged and tried for crimes against humanity.

A PHD doesn't make one smart, and scientists, of all people, should always know that what they don't know is always greater than what they know. I recall a story from a few years ago about a Scientist in the US studying bubonic plague. He genetically modified it to be be harmless in humans, and proceeded to experiment with no bio-hazard controls in place at a public university. Of course, what he did not know was that the modification he made actually optimized the plague for the very genetic traits shown by descendents of plague survivors. Of course he got the plague and died. Luckily, it did not go farther than that.

I know of a researcher who was working sloppily with a form of the plague and managed to die because he had hereditary Iron Overload disease, but I can't find anything about that condition being linked with descendants of plague survivors. Also, the real lesson here is to always follow safety procedures.

Quote:

The logic of creating a deadly flu virus optimized for human transmission - to study it. Is beyond me. Logically they should be charged and tried for crimes against humanity.

So these guys were trying to figure out what it takes for the avian flu to pass between humans, and thus they should be considered criminals of the highest order... what? It's reactionary dipshits like you who are more dangerous to humanity than medical researchers.

This just sounds like reciprocal scaremongering similar to what we see in various other areas of politicised psuedo "science" like global warming, AIDs, the DDT fiasco

Its in the governments interest to keep people paranoid and scared so that more freedoms and rights can be removed to facilitate "speedy" intervention to save us from such pandemic scares not to mention it justifying the huge spending on the bioweapons research centres

And in payment the "scientific concensus" (of carefully chosen scientists) will no doubt be rewarded with endless streams of funding and research opportunities or even jobs heading up the research teams this report will no doubt cause to be created

My guess is the singular dissenting "nutcase" valued integrity above the chance to waste taxpayers money on government nonsense and WMD development projects

This just sounds like reciprocal scaremongering similar to what we see in various other areas of politicised psuedo "science" like global warming, AIDs, the DDT fiasco

Its in the governments interest to keep people paranoid and scared so that more freedoms and rights can be removed to facilitate "speedy" intervention to save us from such pandemic scares not to mention it justifying the huge spending on the bioweapons research centres

And in payment the "scientific concensus" (of carefully chosen scientists) will no doubt be rewarded with endless streams of funding and research opportunities or even jobs heading up the research teams this report will no doubt cause to be created

My guess is the singular dissenting "nutcase" valued integrity above the chance to waste taxpayers money on government nonsense and WMD development projects

(1) the amount of discussion on this has already alerted everyone to the fact that "scary" stuff was found and documented.(2) some nutcase somewhere in the world is already working on making this worse, so publishing this can only serve to educate on the risks(3) publish already

Thing is tho its probably not that scary at all. And publishing it would make that obvious

But restricting it behind shrouds of mystery and hyperbole make it seem ever so much more scarier

And after the last over hyped ficticious pandemic didnt have much of an impact even after the WHO and media were co opted into massively exagerating it maybe theyre just trying a different ruse this time

say unlimited energy could be attained from dripping orange juice on a CPU slowly, but put a couple CPUs in a gallon of juice and you blow up a city. Easy, don't publish the results.

Step 1: Figure out that a small amount of orange juice and a CPU makes unlimited energy (but perhaps not power?).Step 2: Through experimentation or error, someone uses a lot of orange juice and a lot of CPUs, and blows up a city. Hundreds of thousands are killed.Step 3: Launch an investigation on the destruction of the city. Find the Cause. Tell nobody.Step 4: Go to step 2.

Yep. That's a textbook case of "why random people that think they are oh so smart shouldn't actually inhibit the free flow of knowledge."